Rotary reactor for uniform particle coating with thin films

ABSTRACT

A reactor for coating particles includes one or more motors, a rotary vacuum chamber configured to hold particles to be coated, wherein the rotary vacuum chamber is coupled to the motors, a controller configured to cause the motors to rotate the rotary vacuum chamber about an axial axis of the rotary vacuum chamber such that the particles undergo tumbling agitation, a vacuum port to exhaust gas from the rotary vacuum chamber, a paddle assembly including a rotatable drive shaft extending through the rotary vacuum chamber and coupled to the motors and at least one paddle extending radially from the drive shaft, such that rotation of the drive shaft by the motors orbits the paddle about the drive shaft in a second direction, and a chemical delivery system including a gas outlet on the paddle configured inject process gas into the particles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/438,371, filed on Jun. 11, 2019, which claims priority to U.S.Provisional Patent Application Ser. No. 62/683,763, filed on Jun. 12,2018, the disclosure of which is incorporated by reference.

TECHNICAL FIELD

This disclosure pertains coating particles, e.g., particles that includeactive pharmaceutical ingredients, with thin organic and inorganicfilms.

BACKGROUND

It is of great interest to the pharmaceutical industry to developimproved formulations of active pharmaceutical ingredients (API).Formulation can influence the stability and bioavailability of the APIas well as other characteristics. Formulation can also influence variousaspects of drug product (DP) manufacture, for example, ease and safetyof the manufacturing process.

Numerous techniques for encapsulating or coating API have beendeveloped. Some existing techniques for the coating of API include spraycoating, plasma polymerization, hot wire chemical vapor deposition(CVD), and rotary reactors. Spray coating is an industrially scalabletechnique that has been widely adopted by the pharmaceutical industry.However, coating non-uniformities (both within a particle and fromparticle to particle) prevent the use of these techniques for improvingthe delivery profile or stability of active pharmaceutical ingredients(APIs). Particle agglomeration during spray coating also causessignificant challenges.

Meanwhile, techniques such as plasma polymerization are difficult toscale, applicable only to certain precursor chemistries, and can resultin the degradation of sensitive APIs. Hot wire systems have beendeveloped that utilize a cold substrate as the condensation media forgases and radicals. Rotary reactors include atomic layer deposition(ALD) and initiated CVD (iCVD) reactors. However, ALD reactors aresuitable for inorganic coatings and not for organic polymer coatings,and existing iCVD designs do not adequately prevent API degradation andare not scalable for high volume manufacturing. Other techniques includepolymer mesh coating, pan coating, aerosolized coating, and fluidizedbed reactor coating.

SUMMARY

In general, one innovative aspect of the subject matter described inthis specification can be embodied in a reactor for coating particlesthat includes one or more motors, a rotary vacuum chamber configured tohold multiple particles to be coated, a cylindrical portion of therotary vacuum chamber having an inner diameter, and where the rotaryvacuum chamber is coupled to the one or more motors to rotate the rotaryvacuum chamber in a first direction about an axial axis of thecylindrical portion of the rotary vacuum chamber, a vacuum port toexhaust gas from the rotary vacuum chamber, a paddle assembly includinga rotatable drive shaft extending through the rotary vacuum chamberalong the axial axis of the rotary vacuum chamber and at least onepaddle extending radially from the drive shaft, where the rotatabledrive shaft is coupled to the one or more motors such that rotation ofthe drive shaft by the one or more motors orbits the at least one paddleabout the drive shaft in a second direction, and a chemical deliverysystem configured to inject a process gas into the particles, where theat least one paddle includes a gas outlet of the chemical deliverysystem to inject the process gas into the particles.

Implementations may include one or more of the following features. Insome implementations, rotation in the first direction is in a samedirection of rotation as the rotation in the second direction, e.g.,clockwise or counter-clockwise.

In some implementations, the gas outlet of the chemical delivery systemis located on a trailing edge of the at least one paddle.

In some implementations, a vacuum port is located in-line with the axialaxis of the rotary vacuum chamber.

In some implementations, the at least one paddle is one of multiplepaddles configured to sweep along an entirety of a length of the rotaryvacuum chamber along the axial axis of the rotary vacuum chamber. The atleast one paddle can further include an anti-static brush locatedbetween an outer edge of the paddle and in contact with the surface ofthe inner diameter of the rotary vacuum chamber.

In some implementations, the reactor further includes a port to deliverparticles to or receive particles from the rotary vacuum chamber.

In some implementations, the axial axis of the rotary vacuum chamber isoriented horizontally relative to gravity.

In general, another aspect of the subject matter described in thisspecification can be embodied in a reactor for coating particles thatincludes one or more motors, a rotary vacuum chamber configured to holdmultiple particles to be coated, a cylindrical portion of the rotaryvacuum chamber having an inner diameter, and where the rotary vacuumchamber is coupled to the one or more motors, a controller configured tocause the one or more motors to rotate the rotary vacuum chamber in afirst direction about an axial axis of the cylindrical portion of therotary vacuum chamber at a rotation speed sufficient to force themultiple particles to be centrifuged against the inner diameter of therotary vacuum chamber, a vacuum port to exhaust gas from the rotaryvacuum chamber, a paddle assembly including a rotatable drive shaftextending through the rotary vacuum chamber along the axial axis of therotary vacuum chamber and at least one paddle extending radially fromthe drive shaft, where the rotatable drive shaft is coupled to the oneor more motors such that rotation of the drive shaft by the one or moremotors orbits the at least one paddle about the drive shaft in a seconddirection, and a chemical delivery system configured to inject a processgas into the particles, where the at least one paddle includes a gasoutlet of the chemical delivery system to inject the process gas intothe particles.

In some implementations, the controller is configured to cause the oneor more motors to rotate the rotary vacuum chamber about the axial axisat the rotation speed that is greater than 15 RPM. The rotation speed ofthe drive shaft relative to the rotary vacuum chamber about the axialaxis can be at least 4 rpm.

In some implementations, the reactor further includes a base to supportthe reactor on a mounting surface, and where the rotary vacuum chamberis secured to the base such that the axial axis will be perpendicular tothe mounting surface.

In some implementations, rotation in the first direction is in anopposite direction of rotation as the rotation in the second direction.

In some implementations, the at least one paddle includes a rake-shapedfeature including multiple tines such that the tines of the paddles arein contact with the particles when the chemical delivery system isinjecting the process gas into the particles. The gas outlet of thechemical delivery system can be located on a trailing edge of at leastone tine of the multiple tines of the rake-shaped features of thepaddle. An outer edge of the paddle can be separated from a surface ofthe inner diameter of the rotary vacuum chamber by a gap, e.g., a 1-3 mmgap.

In some implementations, the at least one paddle includes a T-shapedfeature including a segment parallel to the surface of the innerdiameter of the rotary vacuum chamber. In general, another aspect of thesubject matter described in this specification can be embodied inmethods that include the actions of dispensing particles into a rotaryvacuum chamber, rotating the rotary vacuum chamber along an axial axisof the rotary vacuum chamber in a first direction such that theparticles form a toroid on an inner wall of the rotary vacuum chamber,evacuating the chamber through a vacuum port in the rotary vacuumchamber aligned on the axial axis of the rotary vacuum chamber, rotatinga paddle assembly in a second direction such that multiple paddles orbita drive shaft, injecting a process gas into the particles throughmultiple gas outlets located on the multiple paddles.

In some implementations, the methods comprise coating the particles byatomic layer deposition or molecular layer deposition. In general,another aspect of the subject matter described in this specification canbe embodied in a reactor that includes one or more motors, a rotaryvacuum chamber configured to hold multiple particles to be coated, acylindrical portion of the rotary vacuum chamber having an innerdiameter, and where the rotary vacuum chamber is coupled to the one ormore motors, a controller configured to cause the one or more motors torotate the rotary vacuum chamber in a first direction about an axialaxis of the cylindrical portion of the rotary vacuum chamber at arotation speed such that the particles undergo tumbling agitation, avacuum port to exhaust gas from the rotary vacuum chamber, a paddleassembly including a rotatable drive shaft extending through the rotaryvacuum chamber along the axial axis of the rotary vacuum chamber and atleast one paddle extending radially from the drive shaft, where therotatable drive shaft is coupled to the one or more motors such thatrotation of the drive shaft by the one or more motors orbits the atleast one paddle about the drive shaft in a second direction, and achemical delivery system configured to inject a process gas into theparticles, where the at least one paddle includes a gas outlet of thechemical delivery system to inject the p gas into the particles.

In some implementations, the controller is configured to cause the oneor more motors to rotate the rotary vacuum chamber about the axial axisat the rotation speed that is less than 6 rpm. The rotation speed of thedrive shaft relative to the rotary vacuum chamber about the axial axiscan be selected such that the relative motion of the paddles 158 withinthe powder does not cause milling and/or damage to the powders duringthe rotary motion(s) of the rotary vacuum chamber and paddle assembly.

In some implementations, the reactor further includes a stationaryvacuum chamber, where the rotary vacuum chamber is disposed within thestationary vacuum chamber.

In some implementations, the reactor further includes a vacuum pumpcoupled to the stationary vacuum chamber and coupled to the vacuum portto exhaust gas from the rotary vacuum chamber. The chemical deliverysystem and the one or more motors can be coupled to the stationaryvacuum chamber.

In some implementations, the rotary vacuum chamber further includes asurface of the inner diameter of the rotary vacuum chamber havinghorizontal or angled baffles.

In general, another aspect of the subject matter described in thisspecification can be embodied in methods that include the actions ofdispensing particles into a rotary vacuum chamber, rotating the rotaryvacuum chamber along an axial axis of the rotary vacuum chamber in afirst direction such that the particles fill a lower portion of therotary vacuum chamber when the rotary vacuum chamber is rotating in thefirst direction, evacuating the chamber through a vacuum port in therotary vacuum chamber aligned on the axial axis of the rotary vacuumchamber, rotating a paddle assembly in a second direction such thatmultiple paddles orbit a drive shaft, and injecting a process gas intothe particles through multiple gas outlets located on the multiplepaddles.

In some implementations, the methods include coating the particles byatomic layer deposition or molecular layer deposition.

In some implementations, the particles include a core containing a drug.In some implementations, the rotary vacuum chamber is configured toperform initiated chemical vapor deposition.

In some implementations, the methods further include depositing anorganic or inorganic coating over the particles. The organic orinorganic coating can be an inorganic metal oxide. The organic orinorganic coating can be an organic polymer.

Implementations may include, but are not limited to, one or more of thefollowing possible advantages. Particles, e.g., API particles, can becoated with in a high volume manufacturing process, thereby providinglower cost of manufacturing and reduced drug product prices. Particlescan be coated with thin layer(s), thus providing a drug product with anadvantageous volume fraction of API. In addition, the process can resultin layer(s) encapsulating the API that are uniform within a particle andfrom particle-to-particle, providing more consistent properties to thedrug formulations.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic front view of an example reactor for ALD and/orCVD coating of particles, e.g., drugs, that includes a rotary vacuumchamber.

FIG. 2 is a schematic side view of the reactor of FIG. 1. FIG. 2 can betaken along line Q-Q in FIG. 1.

FIG. 3A is a schematic side view of another example reactor for ALDand/or CVD coating of particles, e.g., drugs, that includes avertically-oriented rotary vacuum chamber.

FIG. 3B is a schematic side view of another example reactor for ALDand/or CVD coating of particles, e.g., drugs, that includes avertically-oriented rotary vacuum chamber.

FIG. 4 is a schematic front view of another example reactor for ALDand/or CVD coating of particles, e.g., drugs, that includes a rotaryvacuum chamber.

FIG. 5 is a schematic side view of the reactor of FIG. 4. FIG. 5 can betaken along line Q-Q in FIG. 4.

FIGS. 6A-6C are schematics of various views of a rake-shaped paddle.

FIGS. 6D-6G are schematics of various views of a T-shaped paddle withand without an anti-static brush component.

FIGS. 7A and 7B are schematic side views of the reactor systems of FIGS.1-5 with T-shaped paddles.

FIG. 8 is a flow diagram of an example process for utilizing the reactorsystem to coat particles.

Like reference numbers and designations in the various drawings indicatelike elements.

DETAILED DESCRIPTION

There are various methods for encapsulating API particles. In manycases, these methods result in a coating that is relatively thick. Whilesuch coatings can impart desirable properties, the high ratio of coatingto API can make it difficult to create a drug product in which thevolume fraction of API is as high as desired. In addition, the coatingencapsulating the API can be non-uniform, making it difficult to provideformulations with consistent properties.

Furthermore, coating techniques that can provide satisfactoryconsistency have not be scalable for industrial manufacturing.

An approach that may address these issues is to use a rotary “drum” inwhich particles are centrifuged against an inner wall of the rotary drumthrough rotary motion of the drum in a first direction, and in whichpaddles rotating in a second direction (e.g., a same or an oppositedirection as the first direction) agitate the particle bed. Process gascan be injected into the particle bed through gas outlets located on thepaddles. This can force process gas to percolate through the particlebed, which can improve uniformity of coating across particles.

Another approach that may address these issues is to use a rotary vacuumchamber “drum” in which particles are agitated both by a rotation of therotary vacuum chamber and by paddles of a paddle assembly that isrotating with respect to the rotary vacuum chamber, and where processgas is injected into the particles through gas outlets located on thepaddles. This can force process gas to percolate through the particles,which can improve uniformity of coating across particles.

Drug

The term “drug,” in its broadest sense includes all small molecule(e.g., non-biologic) APIs. The drug could be selected from the groupconsisting of an analgesic, an anesthetic, an anti-inflammatory agent,an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, anantibiotic, an anticancer agent, an anticoagulant, an antidepressant, anantidiabetic agent, an antiepileptic, an antihistamine, an antitussive,an antihypertensive agent, an antimuscarinic agent, an antimycobacterialagent, an antineoplastic agent, an antioxidant agent, an antipyretic, animmunosuppressant, an immunostimulant, an antithyroid agent, anantiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, anastringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent,a blood product, a blood substitute, a bronchodilator, a bufferingagent, a cardiac inotropic agent, a chemotherapeutic, a contrast media,a corticosteroid, a cough suppressant, an expectorant, a mucolytic, adiuretic, a dopaminergic, an antiparkinsonian agent, a free radicalscavenging agent, a growth factor, a haemostatic, an immunologicalagent, a lipid regulating agent, a muscle relaxant, aparasympathomimetic, a parathyroid calcitonin, a biphosphonate, aprostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, ananti-allergic agent, an appetite stimulant, an anoretic, a steroid, asympathomimetic, a thyroid agent, a vaccine, a vasodilator and axanthine.

Exemplary types of small molecule drugs include, but are not limited to,acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasonepropionate, salmeterol, pazopanib HC1, palbociclib, and amoxicillinpotassium clavulanate.

Pharmaceutically acceptable excipients, diluents, and carriers

Pharmaceutically acceptable excipients include, but are not limited to:

-   (1) surfactants and polymers including: polyethylene glycol (PEG),    polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinylalcohol,    crospovidone, polyvinylpyrrolidone-polyvinylacrylate copolymer,    cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl    cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl    cellulose phthalate, polyacrylates and polymethacrylates, urea,    sugars, polyols, carbomer and their polymers, emulsifiers, sugar    gum, starch, organic acids and their salts, vinyl pyrrolidone and    vinyl acetate;-   (2) binding agents such as cellulose, cross-linked    polyvinylpyrrolidone, microcrystalline cellulose;-   (3) filling agents such as lactose monohydrate, lactose anhydrous,    microcrystalline cellulose and various starches;-   (4) lubricating agents such as agents that act on the flowability of    a powder to be compressed, including colloidal silicon dioxide,    talc, stearic acid, magnesium stearate, calcium stearate, silica    gel;-   (5) sweeteners such as any natural or artificial sweetener including    sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and    acesulfame K;-   (6) flavoring agents;-   (7) preservatives such as potassium sorbate, methylparaben,    propylparaben, benzoic acid and its salts, other esters of    parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl    or benzyl alcohol, phenolic chemicals such as phenol, or quarternary    compounds such as benzalkonium chloride;-   (8) buffers;-   (9) Diluents such as pharmaceutically acceptable inert fillers, such    as microcrystalline cellulose, lactose, dibasic calcium phosphate,    saccharides, and/or mixtures of any of the foregoing;-   (10) wetting agents such as corn starch, potato starch, maize    starch, and modified starches, and mixtures thereof;-   (11) disintegrants; such as croscarmellose sodium, crospovidone,    sodium starch glycolate; and-   (12) effervescent agents such as effervescent couples such as an    organic acid (e.g., citric, tartaric, malic, fumaric, adipic,    succinic, and alginic acids and anhydrides and acid salts), or a    carbonate (e.g., sodium carbonate, potassium carbonate, magnesium    carbonate, sodium glycine carbonate, L-lysine carbonate, and    arginine carbonate) or bicarbonate (e.g. sodium bicarbonate or    potassium bicarbonate)

Metal Oxide Material

The term “metal oxide material,” in its broadest sense includes allmaterials formed from the reaction of elements considered metals withoxygen-based oxidants. Exemplary metal oxide materials include, but arenot limited to, aluminum oxide, titanium dioxide, iron oxide, galliumoxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide,tantalum oxide, lanthanum oxide, and zirconium dioxide. Exemplaryoxidants include, but are not limited to, water, ozone, and inorganicperoxide.

Atomic Layer Deposition (ALD)

Atomic layer deposition is a thin film deposition technique in which thesequential addition of self-limiting monolayers of an element orcompound allows deposition of a film with thickness and uniformitycontrolled to the level of an atomic or molecular monolayer.Self-limited means that only a single atomic layer is formed at a time,and a subsequent process step is required to regenerate the surface andallow further deposition.

Molecular Layer Deposition (MLD)

Molecular layer deposition is analogous to atomic layer deposition butusing organic precursors and forming organic thin films. During atypical MLD process two homo-bifunctional precursors are used. A firstprecursor is introduced into a chamber. The molecules of the firstprecursor react with reactive groups on the substrate surface via thecorresponding linking chemistry to add a molecular layer of the firstprecursor on the substrate surface with new reactive sites. Afterpurging, a second precursor is introduced and the molecules of thesecond precursor react with the new reactive sites provided by the firstprecursor generating a molecular layer of the first precursor linked tothe second precursor. This is followed by another purge cycle.

Reactor System

FIGS. 1-2 illustrate a reactor system 100 for coating particles with athin-film coating. The reactor system 100 can perform the coating usingALD and/or MLD coating conditions. The reactor system 100 permits adeposition process (ALD or MLD), to be performed at higher (above 50°C., e.g., 50-100° C.) or lower processing temperature, e.g., below 50°C., e.g., at or below 35° C. For example, the reactor system 100 canform thin-film metal oxides on the particles primarily by ALD attemperatures of 22-35° C., e.g., 25-35° C., 25-30° C., or 30-35° C. Ingeneral, the particles can remain or be maintained at such temperatures.This can be achieved by having the reactant gases and/or the interiorsurfaces of the reactor chamber remain or be maintained at suchtemperatures. For example, heating can be achieved by a heater cartridgeembedded in chamber body, by water channel in chamber body with use ofheat exchanger, or by a heater jacket on the chamber body.

The reactor system 100 includes a stationary vacuum chamber 110 thatencloses a rotary vacuum chamber 112. The stationary vacuum chamber 110is enclosed by outer chamber walls 114. The rotary vacuum chamber 112 isenclosed by inner chamber walls 116. The chamber walls 114 and 116 canbe a material, e.g., stainless steel, that is inert to the depositionprocess, and/or the interior surfaces of the chamber walls 114 and 116can be coated with a material that is inert to the deposition process.

A cross-section of the rotary vacuum chamber 112 (e.g., as viewed alongthe central axis of the cylinder) of the rotary vacuum chamber can beuniform along the length of the chamber 112 (the length is along thecentral axis of the cylinder). This can help ensure uniform gas flowalong the length of the chamber.

The stationary vacuum chamber 110 can include one or more vacuum ports118 for exhausting gas, e.g., process gas, from the stationary chamber110 and rotary vacuum chamber 112. The stationary vacuum chamberincludes a gas inlet port 120 coupled to a chemical delivery system 122located outside of the stationary vacuum chamber 110. The gas inlet port120 further couples process gas via a gas delivery manifold 124 from thegas inlet port 120 located at the stationary vacuum chamber to a gasinlet port 126 located on a central axis 165 of the rotary vacuumchamber 112. The gas delivery manifold 124 is depicted schematically in

FIG. 1 as entering the chamber from along the perimeter of thecylindrical chamber, however, in the embodiment described with referenceto FIGS. 1 and 2, the gas delivery manifold is in-line with the centralaxis of the chamber 112 through a passage within the drive shaft 156(e.g., as depicted in FIG. 2).

System 100 includes one or more motors 130 a, 130 b outside of thestationary vacuum chamber 110 that are configured to provide torque thattranslates into rotary motion of one or more components of the system100. Motors 130 a, 130 b can be, for example, a drum motor 130 a and apaddle motor 130 b. Motors 130 a and 130 b can be, for example,brushless direct current (DC) DC motors. In some implementations, motors130 a and 130 b have gear reduction built in, e.g., at a ratio of 20:1.

The drum motor 130 a is coupled to the rotary vacuum chamber 112 andconfigured to provide torque that is translated into rotary motion ofthe rotary vacuum chamber 112 during operation of system 100. The paddlemotor 130 b is coupled to a paddle assembly 132 and configured toprovide torque that is translated into rotary motion of the paddleassembly during operation of system 100. Though described with referenceto FIGS. 1 and 2 as a drum motor 130 a and a paddle motor 130 b, feweror more motors can be configured to provide torque that translates intorotary motion of the one or more components of the system 100.

System 100 includes a vacuum source 134 (e.g., one or more vacuum pumps)coupled to vacuum port 118 via a gas exhaust manifold 136. In someimplementations, a gas source 139 is coupled to the gas exhaust manifold136, e.g., a purge gas to dilute process gas that is exhausted from thesystem 100. Gas exhaust manifold 136 is configured to establish vacuumwithin the stationary vacuum chamber 110 and rotary vacuum chamber 112.The vacuum source 134 can be an industrial vacuum pump sufficient toestablish pressures less than 1 Torr, e.g., 1 to 100 mTorr, e.g., 50mTorr. The vacuum source 134 permits the chambers 110, 112 to bemaintained at a desired pressure, and permits removal of reactionbyproducts and unreacted process gases.

The chemical delivery system 122 includes multiple fluid sources 138coupled by respective delivery tubes 140, controllable valves 142, and afluid supply line 144. The chemical delivery system 122 delivers fluidto the gas delivery manifold 124 that inject the fluid in a vapor forminto the rotary vacuum chamber 112 via the gas inlet port 126. The gasinlet port 126 is further coupled to a paddle manifold 164 which iscoupled to one or more gas outlets 166 (as depicted in FIG. 2) that arelocated on at least one paddle 158 of the paddle assembly 132. Thechemical delivery system 122 can include a combination of restrictors,gas flow controllers, pressure transducers, and thermal mass flowcontrollers/meters to provide controllable flow rate of the variousgasses into the rotary vacuum chamber 112. The chemical delivery system122 can also include one or more temperature control components, e.g., aheat exchanger, resistive heater, etc., to heat or cool the variousgasses before they flow into the chamber 112.

The chemical delivery system 122 can include five fluid sources 138 a,138 b, 138 c, 138 d, 138 e. Two of the fluid sources, e.g., fluidsources 138 a, 138 b, can provide the two chemically differentprecursors or reactants for the deposition process for forming a metaloxide layer on the particles. For example, the first fluid source 138 acan provide trimethylaluminum (TMA) or titanium tetrachloride (TiCl4),whereas the fluid gas source 138 b can provide water. Another two of thefluid sources, e.g., fluid sources 138 c, 138 d, can provide the twochemically different precursors or reactants for the deposition processfor forming a polymer material on the metal oxide layer. For example,the third fluid source 138 c can provide adipoyl chloride, and thefourth gas source 138 d can provide ethylene diamine. One of the fluidsources, e.g., the fifth fluid source 138 e, can provide an inert gas,e.g., argon or N₂, for purging between cycles or half-cycles in thedeposition process.

Although FIG. 1 illustrates five fluid sources, the use of fewer gassources could still be compatible with deposition of a metal oxide orpolymer layer, and use of more gas sources could enable formation of aneven wider variety of laminate structures.

For one or more of the fluid sources, the chemical delivery system 122delivers the precursor or reactant in liquid form to the gas deliverymanifold 124. The chemical delivery system 122 can include a vaporizer146 to convert the liquid to vapor immediately before the precursor orreactant enters a gas inlet 120. This reduces upstream pressure loss toenable more pressure loss to occur across the particles 148 within thechamber 112. The more pressure loss that occurs across the particles148, the lower the injection apertures can be place, and the more likelythat all of the precursor will be reacted as it traverses the particlebed for a given flow rate. The vaporizer 146 can be immediately adjacentthe outer wall of the stationary vacuum chamber 110, e.g., secured to orhoused adjacent to the gas inlet port 120.

As shown in FIG. 1, gas delivery manifold 124 can be utilized to supplymultiple precursor or reactant fluid sources 138. Manifold 151 isfluidically connected to gas inlet port 120.

The rotary vacuum chamber 112 is encapsulated within and supported bythe stationary vacuum chamber 110. The rotary vacuum chamber 112includes an inner surface 150 along an inner diameter of the chamberwalls 116. In some implementations, as depicted in FIGS. 1 and 2, therotary vacuum chamber includes a cylindrical portion, where an axis ofrotation is aligned on a center axis of the cylinder. The rotary vacuumchamber 112 is connected to a vacuum tight rotary union, and isconnected to the stationary vacuum chamber 110 by screws inside therotary vacuum chamber 112 via the rotary motion feedthrough 129, asdepicted in FIG. 2. Referring now to FIG. 2, the rotary vacuum chamber112 is coupled to one or more motors, e.g., drum motor 130 a, where thedrum motor 130 a is operable to generate torque that can translate intorotary motion of the rotary vacuum chamber in a first direction 152(e.g., clockwise with respect to an axial axis Q-Q. The coupling betweenthe rotary vacuum chamber 112 and the one or more motors can be througha rotary motion vacuum feedthrough 128, as depicted in FIG. 2. One ormore mechanical couplings 154 can be utilized between the drum motor 130a and the rotary vacuum chamber 112 to translate a torque output fromthe motor 130 a into a rotary motion in the first direction 152 of therotary vacuum chamber 112. In some implementations, mechanical couplings154 can be a belt and pulley system, where a belt can have compliance toallow for some misalignment and run out of the drum motor 130 a and therotary vacuum chamber 112. Motion of the rotary vacuum chamber 112 canbe clockwise (CW), counter-clockwise (CCW), or can alternate between CWand CCW. In some implementations, port 113 of the rotary vacuum chamberis coupled to the rotary motion feedthrough 129 by a key block totransfer torque between the drum motor 130 a and the rotary vacuumchamber 112.

Paddle assembly 132 includes a drive shaft 156 and one or more paddles158 coupled to the drive shaft 156. Drive shaft 156 is oriented along anaxial axis Q-Q of the rotary vacuum chamber 112. Paddles 158 are affixedto the drive shaft 156 along the length of the drive shaft 156. Thepaddles are positioned such that an outer surface 115 of the paddles 158is spaced by a threshold distance, e.g., a gap 117, from the innersurface 150 of the rotary vacuum chamber 112. Details of the paddles 158are discussed below.

The paddle assembly 132 is coupled to one or more motors outside thevacuum chamber 110, e.g., paddle motor 130 b, via the rotary vacuumfeedthrough 128 (e.g., including vacuum-compatible bearings). The paddlemotor 130 b is configured to apply torque to the drive shaft 156 suchthat the drive shaft 156 rotates about a center axial 118 axis alignedwith axis Q-Q of the drive shaft 156 in a second direction 160. One ormore mechanical couplings 162 can be utilized between the paddle motor130 b and the drive shaft 156 to translate a torque output from themotor 130 b into a rotary motion in the second direction 160 (e.g.,counter clockwise with respect to the axial axis Q-Q) of the paddleassembly 132. In some implementations, mechanical couplings 162 can be abelt and pulley system, where a belt can have compliance to allow forsome misalignment and run out of the paddle motor 130 b and the driveshaft 156 of the paddle assembly 132. Motion of the drive shaft 156 canbe clockwise (CW) or counter-clockwise (CCW).

In some implementations, the rotary motion vacuum feedthrough 128 is abearing vacuum seal that can be used to seal the stationary vacuumchamber 110 from the external environment. The drive shaft 156 can thenpass through a portion of the stationary vacuum chamber 110 and througha port 113 of the rotary vacuum chamber 112 such that the drive shaft156 to rotate freely with respect to the rotary vacuum chamber 112. Alip seal can be located between the port 113 and the rotary motionfeedthrough 129 to prevent powder in the rotary vacuum chamber 112 fromtraveling down the drive shaft 156 to the bearings of the rotary motionfeedthrough 129.

In some implementations, the first direction 152 and the seconddirection 160 are opposite directions, e.g., clockwise andcounter-clockwise. The first direction 152 and second direction 160 caninstead be in a same direction, e.g., both clockwise or bothcounter-clockwise.

Paddle assembly 132 further includes a paddle manifold 164 that iscoupled to the gas inlet port 126. The paddle manifold 164 connects theinlet port 126 to one or more gas outlets 166 located on at least onepaddle 158 of the paddle assembly 132. This permits the process gas(e.g., reactant or precursor gas) to flow from the chemical distributionsystem 122 and be injected into the rotary vacuum chamber 112 via theoutlets on the paddle 158. In some implementations, multiple paddles 158a, 158 b, 158 c of the paddle assemble 132 each include multiple gasoutlets 166 coupled to the paddle manifold 164 such that process gas isinjected into the rotary vacuum chamber via the multiple gas outlets166. The multiple paddles 158 of the paddle assembly 132 can bedistributed along the axial axis of the drive shaft 156, e.g., spaced atuniform intervals, to ensure an even distribution of process gasinjected into the rotary vacuum chamber 112 via the gas outlets 166located on each of the multiple paddles 158.

As depicted in FIG. 2 the paddles 158 of the paddle assembly 132 areoriented on the drive shaft 156 such that the alignment of the paddlesresults in little or no lateral gaps of interaction between the paddles158 and the particles 148. In some implementations, as depicted in FIG.2, only the portion 159 of the paddles 158 of the paddle assembly 132are in contact with the particles 148 during the operation of the system100.

In some implementations, process gas is injected into the rotary vacuumchamber 112 from the gas outlets located on the paddles 158 in adirection 168 opposite an instantaneous motion of the paddles 158 due torotation of the paddle assembly 132 in the second direction 160. Inother words, the multiple gas outlets 166 are located on a trailing edgeof the paddles 158 such that process gas is injected into the rotaryvacuum chamber 112 from the gas outlets 166 in a direction that isopposite the rotary motion of the paddles 158. In one example, thepaddle assembly 132 is rotating in a clockwise direction and the processgas is injected into the rotary vacuum chamber 112 in acounter-clockwise direction. Further details of the configuration of thegas outlets are discussed below.

An inert carrier gas, e.g., N₂, can flow from one of the fluid sources,e.g., the fluid source 138e, into the paddle manifold 164. In operation,the carrier gas can flow continuously into the paddle manifold 164,i.e., whether or not the precursor or reactor gas is flowing into thepaddle manifold 164. When the precursor or reactor gas is not beinginjected into the chamber 112 through the manifold 164, the flow of thecarrier gas can prevent backstreaming into the gas outlets 166 of theanother precursor or reactor gas that is being injected from anothermanifold. The flow of carrier gas can also prevent fouling of the gasoutlets 166, e.g., blockage of the aperture, by the particles 148. Inaddition, the carrier gas can provide the purge gas for the purgeoperation when the precursor or reactor gas is not being injected intothe chamber 112.

The flow of carrier gas into the vaporizer 146 when the precursor gas isalso flowing can improve vaporization of the precursor or reactantliquid. Without being limited by any particular theory, the carrier gasflow can assist in shearing the liquid during aerosolization, which canlead to smaller droplet size, which can be vaporized more quickly. Flowof the carrier gas into the paddle manifold 164 when the precursor gasis also flowing can assist in drawing precursor gas out of the vaporizer146.

In some implementations, one or more temperature control components areintegrated into the inner chamber walls 116 to permit control of thetemperature of the rotary vacuum chamber 112. For example, resistiveheater, a thermoelectric cooler, a heat exchanger, or coolant flowing incooling channels in the chamber wall, or other component in or on theside walls 116.

System 100 further includes a controller 170 that is operable to controlthe actions of at least the chemical distribution system 122 and the oneor more motors 130 a, 130 b. Controller 170 can be configured to operatethe paddle motor 130 b to generate a rotary motion of the paddleassembly 132 in the second direction 160 at rotational speeds up to 200rotations per minute (rpm). Controller 170 can be further configured tooperate the drum motor 130 a to generate a rotary motion of the rotaryvacuum chamber 112 in the first direction 152 at rotational speeds up to200 rpm, for example, ranging betweenl-60 (rpm). In someimplementations, the controller 170 is configured to operate the drummotor 130 a to produce a rotational speed of the rotary vacuum chamber112 that exceeds a threshold rotational motion, e.g., that is greaterthan 15 rpm.

As depicted in FIGS. 1 and 2, the rotation rate is sufficiently highthat particles 148 are centrifugally forced against the inner surface150 of the rotary vacuum chamber 112 (this can be referred to as “fast”rotary motion). This can result in a toroidal bed of particles 148 onthe inner surface 150. An amount of compression of the bed of particlesformed by the fast rotary motion of the rotary vacuum chamber 112 candepend, for example, of the rotational speed of the rotary vacuumchamber 112. The controller 170 can also be coupled to various sensors,e.g., pressure sensors, flow meters, etc., to provide closed loopcontrol of the rotation rate of the chamber and the pressure of thegasses in the chamber 110.

In some implementations, rotational speed of the drum motor 130 a can beselected based on a desired forced to be experienced by the particles148 present within the rotary vacuum chamber 112 during operation of thereactor as described by equation (1)

F∝α_(i)*r   (1)

where F is a force experienced by the particles 148 that is proportionalto the acceleration of the rotary vacuum chamber 112 (e.g., in rotationsper minute-squared (rpm²)) multiplied by a radius r of the rotary vacuumchamber 112. Above a threshold amount of force experienced by theparticles 148, the particles 148 will be centrifugally forced againstthe inner surface 150 of the rotary vacuum chamber 112. An amount offorce F depends in part on a radius of the rotary vacuum chamber 112that can range, for example, between 100-300 mm. In one example, aradius of the rotary vacuum chamber 112 is 215 mm.

In general, the controller 170 is configured to operate the reactorsystem 100 in accord with a “recipe.” The recipe specifies an operatingvalue for each controllable element as a function of time. For example,the recipe can specify the times during which the vacuum source 132 isto operate, the times of and flow rate for each gas source 138 a-138 e,the rotation rate of the rotary vacuum chamber 114 and the drive shaft156 as set by the motors 130 a, 130 b, etc. The controller 170 canreceive the recipe as computer-readable data (e.g., that is stored on anon-transitory computer readable medium).

The system 100 further includes a first loading port 172 located on thestationary vacuum chamber 110 and a second loading port 174 located onthe rotary vacuum chamber 112 which can be aligned to allow access tothe inside of the rotary vacuum chamber 112 in order to load particles148 to be processed. The first loading port 172 and second loading port174 can be sealed during operation of the reactor system 100 such thatthe ports hold against vacuum established within the respective vacuumchambers. Methods for operation of the reactor system 100 are describedin further detail below.

The system 100 further includes a particle filter 176 that allows toexhaust gas from the rotary vacuum chamber 112 via the vacuum port 118located in the stationary vacuum chamber 110. In some implementations,as depicted in FIG. 2 the vacuum port 118 for the system 100 is in-linewith the drive shaft 156 along the Q-Q axis. In addition, the system 100can include a filter cleaner to clear particles off the filter 176. Asone example, the filter cleaner can be a mechanical knocker to strikethe filter; this make shake particles off the filter. As anotherexample, gas source 139 can periodically provide a pulse of inert gas,e.g., nitrogen, into the exhaust manifold 136 between the vacuum port118 and the vacuum source 134. The pulse of gas travels through thefilter 176 back toward the chamber 112 and can blow the particles off ofthe filter 176. Isolation valves 139 a, 139 b can be used to ensure thatonly one of the gas source 138 or vacuum source 134 is fluidicallycoupled at a time to the exhaust manifold 136.

The reactor system 100 can include a base 173 to support the reactor 100on a mounting surface 171. In some implementations, the reactor system100 is secured to the base 173 such that the axial axis 165 isperpendicular to the mounting surface 171. As a result, assuming ahorizontal mounting surface 171, the drive shaft and axial axis 165 areparallel to gravity, i.e., are vertically oriented. FIG. 3A is aschematic side view of another example reactor for ALD and/or CVDcoating of particles, e.g., drugs, that includes a vertically-orientedrotary vacuum chamber 100′.

In some embodiments, as depicted in FIGS. 1 and 2, the reactor system100 is secured to the base 173 such that the axial axis 165 and thedrive shaft 156 are perpendicular to the mounting surface 171. As aresult, assuming a horizontal mounting surface, the axis of rotation ofthe rotary vacuum chamber 114 is perpendicular to gravity.

As depicted in FIG. 3A, the vertical drive shaft 157 is coupled to thevertically-oriented rotary vacuum chamber 135 at a bottom surface 174 ofthe rotary vacuum chamber 135. In some implementations, the verticaldrive shaft 157 can instead by coupled to the vertically-oriented rotaryvacuum chamber 135 at a surface 175 of the rotary vacuum chamber 135.

During operation of the reactor system 100′ depicted in FIG. 3A, thecontroller 170 is configured to operate the drum motor 130 a to producerotational speed of the vertically-oriented rotary vacuum chamber 135that is sufficiently high that particles 148 are centrifugally forcedagainst the inner surface 150 of the vertically-oriented rotary vacuumchamber 135. This can result in a toroidal bed of particles 148 on theinner surface 150.

In some implementations, a vacuum port 119 for exhausting gas from thechamber 113 is located on a side of the stationary vacuum chamber 110.The vacuum port 119 can be oriented opposite the rotary motion vacuumfeedthrough 128 that couples the drive shaft 157 to into the chamber113.

FIG. 3B is a schematic side view of another example reactor for ALDand/or CVD coating of particles, e.g., drugs, that includes avertically-oriented rotary vacuum chamber 100″. As depicted in FIG. 3B,the vertical drive shaft 157 is coupled to the vertically-orientedrotary vacuum chamber 135 at a bottom surface 174 of the rotary vacuumchamber 135. In some implementations, the vertical drive shaft 157 caninstead by coupled to the vertically-oriented rotary vacuum chamber 135at a surface 175 of the rotary vacuum chamber 135.

Reactor 100″ additionally includes an inner wall 149 (e.g., defining aninner circumference) within the rotary vacuum chamber 135, where theinner wall 149 separates a first region 151 of the rotary vacuum chamberthat is configured to receive particles 148 from a second region 153that is not configured to receive particles 148. Paddles 158 of thepaddle assembly 133 are coupled to the drive shaft 157 such that thepaddles 158 and at least one gas outlet 166 located on the paddles 158are located partially within the first region 151.During operation ofthe reactor system 100′ depicted in FIG. 3B, the controller 170 isconfigured to operate the drum motor 130 a to produce rotational speedof the vertically-oriented rotary vacuum chamber 135 such that theparticles within the chamber 135 do not form a toroid against the innersurface 150 of the rotary vacuum chamber 135.

FIGS. 4-5 illustrate another example reactor system 100′″ for coatingparticles with a thin-film coating. The reactor system 100′″ can performthe coating using ALD and/or MLD coating conditions.

In some implementations, a rotational speed of the rotary vacuum chamber112 is less than a threshold rotational speed, e.g., less than 15 rpm,such that particles 148 within the rotary vacuum chamber experiencetumbling agitation while the rotary vacuum chamber 112 is in rotationalmotion. For example, the chamber 112 can rotate at 6-15 rpm. Atsufficiently low rotation speeds, the particles within the chamber 112do not form a toroid against the inner surface 150 of the rotary vacuumchamber 112. A controller 182 is configured to operate the drum motor130 a to produce rotational speed of the rotary vacuum chamber 112 inthe first direction 152 that is less than the threshold rotationalspeed.

During operation of the reactor system 100′″, particles loaded into therotary vacuum chamber 112 form a particle bed 178 located below a lowerportion 180 of the interior of the rotary vacuum chamber 112, relativeto gravity. As the rotary vacuum chamber 112 rotates about the axialaxis defined by Q-Q, the particles in the particle bed 178 undergo atumbling agitation. Some portion of the particles may be temporarilyelevated due to rotation, but fall back into the powder bed due togravity. Thus, most or all of the particles remain in the lower portion180 of the rotary vacuum chamber 112.

In some implementations, the rotary vacuum chamber 112 rotates atrotational speeds less than a threshold rotational speed, e.g., at aspeed of 6-15 RPM. The controller 170 can be configured to operate thedrum motor 130 a to generate rotary motion in the rotary vacuum chamber112 in alternating directions, e.g., alternating between clockwise andcounter-clockwise rotary motion. This can assist in agitation of theparticles to improve uniformity of the coating. A rate of alternatingdirections, e.g., an amount of time for which the chamber 112 isrotating in a first direction vs a second direction, can be selectedbased on the particular recipe and/or particles 178 that are beingcoated by the reactor system 100′″.

In some implementations, as depicted in FIGS. 4 and 5, one or morepaddles 158 of the paddle assembly 132 are not in contact with theparticle bed 178 at a given time during the rotation of the paddleassembly about the axial axis defined by Q-Q. For example, paddle 158 ais in contact with the particle bed 178 and paddles 158 b and 158 c arenot in contact with the particle bed 178 at an instant of the rotationof the paddle assembly 132.

In some implementations, as depicted in FIG. 4, the rotary vacuumchamber 112 rotates in a first direction 152 and the paddle assembly 132rotates in a second, opposite direction 160. A center of rotation ofeach of the rotary vacuum chamber 112 and the paddle assembly 132 is asame axial axis aligned with a center of the cylindrical portion of therotary vacuum chamber 112.

In some implementations, the rotary vacuum chamber 112 includes baffleson an inner surface 150 of the chamber 112, where the baffles can beoriented to move particles from the particle bed 178 from a first sideof the rotary vacuum chamber 112 to a second side of the rotary vacuumchamber 112 as the rotary vacuum chamber 112 rotates about the axialaxis at a rotational speed in the first direction 152.

As discussed above with reference to FIGS. 1 and 2, a paddle 158 of thepaddle assembly 132 can have various configurations. Described here arethree variations on the paddle design for the paddle assembly. However,alternative embodiments having similar functionality can be imagined. Ingeneral, shape and orientation of paddles 158 of the paddle assembly 132are selected such that the paddles 158 of the paddle assembly 132provide mechanical agitation of particles 148 (and/or particle bed 178)that are present within the rotary vacuum chamber 112 during operationof the reactor system (e.g., reactor systems 100, 100′, 100′″). Thepaddles 158 further include one or more gas outlets 166 located on thepaddles 158 to inject process gas from the chemical distribution system122 into the rotary vacuum chamber 112 during operation of the reactorsystem 100, 100′, 100′″. Paddles 158 are affixed on a drive shaft (e.g.,drive shaft 156) and oriented along the drive shaft 156 to providesubstantially even coverage of mechanical agitation and process gasinjection along a length of the cylindrical portion of the rotary vacuumchamber 112 during operation of the reactor system 100, 100′, 100′″(e.g., during rotational motion of the paddle assembly 132 in the seconddirection 160).

As depicted in FIGS. 1-5, a paddle 158 of the paddle assembly 132 can bea rake-shaped paddle. FIGS. 6A-6C are schematics of various views of arake-shaped paddle 600. As depicted in FIG. 6A, rake-shaped paddle 600includes a base shaft 602 that is coupled to a drive shaft of the paddleassembly (e.g., drive shaft 156 of the paddle assembly 132). The paddlefurther includes a cross-bar 604 coupled to the base shaft 602 of thepaddle 600, and multiple tines 606 each coupled to the cross-bar 604 andextending away from the base 608 of the paddle 600. The multiple tines606 can have length ranging 50-100 mm, e.g., 78 mm. A profile of thetines 606 can be selected such that the tines 606 move gently throughthe powder as the paddle assembly rotates. In one example, the tines 606are tear-drop shaped.

In some implementations, dimensions of the paddle 600 e.g., a length ofthe base shaft 603 and a length 605 of the tines 606, can be selectedsuch that a distance (e.g., gap 117) between an outer surface 607 (e.g.,the outer surface 115) of the tines 606 of the paddle 600 is less than athreshold distance (e.g., 1-3 mm) from an inner surface of the rotaryvacuum chamber (e.g., rotary vacuum chamber 112) when the paddle 600 isaffixed to the drive shaft of the paddle assembly (e.g., drive shaft 156of paddle assembly 132).

Each of the base shaft 602, cross-bar 604, and multiple tines 606 hasinternal tubing and/or passageways 610 that are coupled to the paddlemanifold (e.g., paddle manifold 164). Process gas can flow 612 throughthe base shaft 602, into the cross-bar 604 and further into the multipletines 606 via the internal tubing and/or passageways 610. FIG. 6Bdepicts a “top-down” view C indicating an example location of theinternal tubing and/or passageways 610 within the tines 606 of thepaddle 600.

As depicted in FIG. 6C, the process gas is then injected into the rotaryvacuum chamber (e.g., rotary vacuum chamber 112) via multiple gasoutlets 614 (e.g., gas outlets 166) located on the paddle 600, e.g., oneor more gas outlet 614 located on each tine 606. Gas outlets 614 canhave a diameter ranging 0.5-3 mm, e.g., 1 mm in diameter with a spacingbetween adjacent gas outlets 614 ranging between 5-15 mm, e.g., 8 mmspacing. A number of gas outlets 614 per tine 606 can range between 5-20gas outlets 614, e.g., 7 gas outlets 614 per tine 606. The gas outlets614 can be arranges on the tine 606 along a line that bisects a width ofthe tine 606.

In some implementations, the multiple gas outlets 614 are located on themultiple tines 606 of the paddle 600. For example, each tine 606 canhave a single gas outlet 614. The multiple gas outlets 614 are locatedon a surface indicated by B of each tine 606, corresponding to atrailing edge of the paddle 600 when the paddle 600 is rotating aboutthe second direction (e.g., second direction 160) within the rotaryvacuum chamber 112. Though depicted in FIG. 6C as multiple gas outlets614 aligned along an axis D-D with evenly distributed spacing 616between each gas outlet 614, the multiple gas outlets can be off-setwith respect to each other and/or can have variable spacing.

In some implementations, a paddle of the paddle assembly (e.g., paddleassembly 132) is T-shaped. FIGS. 6D-6G are schematics of various viewsof T-shaped paddle 650 with and without an anti-static brush component664. As depicted in FIG. 6D, T-shaped paddle 650 includes a base shaft652 and a cross-bar 654, where the base shaft 652 is coupled to thedrive shaft of the paddle assembly (e.g., drive shaft 156 of paddleassembly 132), and the cross-bar 654 is located on an end 656 of thebase shaft 652 opposite of a surface where the base shaft 652 is coupledto the drive shaft.

In some implementations, dimensions of the paddle 650 e.g., a length 651of the base shaft 652 and a width 653 of the cross-bar 654, can beselected such that a distance (e.g., gap 117) between a surface 655(e.g., surface 115) of the cross-bar 654 are less than a thresholddistance (e.g., 1-3 mm) from an inner surface of the rotary vacuumchamber (e.g., rotary vacuum chamber 112) when the paddle 650 is affixedto the drive shaft of the paddle assembly (e.g., drive shaft 156 ofpaddle assembly 132).

Each of the base shaft 652 and the cross-bar 654 has internal tubingand/or passageways 610 that are coupled to the paddle manifold (e.g.,paddle manifold 164). Process gas can flow 630 through the base shaft652 and into the cross-bar 654 via the internal tubing and/orpassageways 610. FIG. 6E depicts a “top-down” view C indicating anexample location of the internal tubing and/or passageways 610 withinthe cross-bar 654 of the paddle 650.

As depicted in FIG. 6F, the process gas is then injected into the rotaryvacuum chamber (e.g., rotary vacuum chamber 112) via multiple gasoutlets 658 (e.g., gas outlets 166) located on the paddle 650, e.g., oneor more gas outlet 658 located on each cross-bar 654. Gas outlets 658can have a diameter ranging 0.5 mm-3 mm, e.g., 1 mm diameter with aspacing between gas outlets 658 ranging between 5-15 mm, e.g., 10 mmbetween each gas outlet 658. A number of gas outlets 658 located on eachpaddle 650 can range between 5-20 gas outlets 658, e.g., 8 gas outletsIn some implementations, the multiple gas outlets 658 are located on thecross-bar 654 of the paddle 650, where the multiple gas outlets 658 arelocated on a surface indicated by E of the cross-bar 654, correspondingto a trailing edge of the paddle 650 when the paddle 650 is rotatingabout the second direction (e.g., second direction 160) within therotary vacuum chamber 112. Further detail of a paddle assembly includingT-shaped paddles 650 are discussed below with reference to FIGS. 7A, 7B.

Though depicted in FIG. 6F as multiple gas outlets 654 aligned along anaxis G-G with evenly distributed spacing 660 between each gas outlet658, the multiple gas outlets can be off-set with respect to each otherand/or can have variable spacing. The multiple gas outlets 658 can bedistributed on the trailing edge of the paddle 650 in multiple rowsand/or in multiple patterns on the surface of the trailing edge surfaceof the cross-bar indicated by E, where a configuration of the multiplegas outlets 658 can be selected to optimize an substantially evendistribution of process gas injected into the rotary vacuum chamber bythe paddle assembly (e.g., rotary vacuum chamber 112 by paddle assembly132).

In some implementations, the T-shaped paddle 650 further includes ananti-static brush component 662 located on the outer surface 655 of thecross-bar 654, as depicted in FIG. 6G.

The anti-static brush component 662 can be composed of a semi-flexiblematerial (e.g., a high-temperature inert rubber/plastic, thin aluminumfins, or the like). A material of the anti-static brush 662 can beselected to contact the inner surface of the rotary vacuum chamber inorder to sweep particles (e.g., particles 148 and/or particle bed 178)from the inner surface of the rotary vacuum chamber during the rotarymotion of the paddle assembly. The material of the anti-static brushcomponent 662 can further be selected to avoid damaging the innersurface of the rotary vacuum chamber (e.g., avoid scratching or dentingthe surface) due to the contact between the anti-static brush component662 and the inner surface of the rotary vacuum chamber 112.

The anti-static brush component 662 is located between the end surface655 of the T-shaped paddle 650 and in contact with the inner surface ofthe rotary vacuum chamber (e.g., inner surface 150 of the rotary vacuumchamber 112) when the paddle 650 is affixed and oriented on the driveshaft of the paddle assembly within the rotary vacuum chamber (e.g.,drive shaft 156 of paddle assembly 132 in rotary vacuum chamber 112).

In some implementations, the anti-static brush component 662 includesmultiple fins 664, where a density and/or spacing of the fins 664 of theanti-static brush component 662 can be selected to ensure coverage of anentire length of the inner surface of the rotary vacuum chamber througha complete rotation of the paddle assembly (e.g., 360 degrees) withrespect to the rotary vacuum chamber.

In some implementations, the reactor systems 100, 100′, and 100′″described with reference to FIGS. 1-5 can include T-shaped paddles 650.FIGS. 7A and 7B are schematic side views of the reactor systems of FIGS.1-5 with T-shaped paddles (e.g., T-shaped paddle 650). A gap 117 betweena surface 115 of the cross-bar 654 of the T-shaped paddle 650 and aninner surface 150 of the rotary vacuum chamber 112 can be less than athreshold distance (e.g., less than 3 mm).

In some implementations, a spacing 702 of the T-shaped paddles 650 ofthe paddle assembly 132 along the axial axis Q-Q can be selected suchthat there is substantially even mechanical agitation and process gasinjection across the multiple paddles 650 along the length of thecylindrical portion of the rotary vacuum chamber 112 during rotarymotion operation of the paddle assembly 132. In some implementations,spacing 702 can be zero or less than zero (e.g., T-shaped paddles 650can overlap).

In some implementations, as described with reference to FIG. 7B,T-shaped paddle 650 can include an anti-static brush component 662. FIG.7B is a schematic side view of the reactor systems of FIGS. 1-5 withT-shaped paddles including anti-static brush components. The anti-staticbrush component 662 located on the T-shaped paddle 650 of the paddleassembly 132 is in contact with the inner surface 150 of the rotaryvacuum chamber 112.

Operation of Reactor System

FIG. 8 is a flow diagram of an example process of utilizing the reactorsystem to coat particles. In a first step, particles are dispensed intoa rotary vacuum chamber (802). As described with reference to FIGS. 1-7,reactor system (e.g., reactor systems 100, 100′, and 100′″) include anouter stationary vacuum chamber 110 and inner rotary vacuum chamber 112,where loading ports on each of the stationary vacuum chamber and rotaryvacuum chamber (e.g., loading ports 172, 174) can be aligned to allowfor loading/unloading of particles to be coated into the reactor system.

The particles (e.g., particles 148) can have a solid core comprising adrug, e.g., one of the drugs discussed above. The solid core canoptionally also include an excipient. Once any loading ports (e.g.,loading ports 172, 174) are sealed, a controller (e.g., controller 170)operates the reactor system (e.g., reactor systems 100, 100′, 100′″)according to a recipe in order to form the thin-film metal oxide layersand/or thin polymer layers on the particles.

The rotary vacuum chamber is rotated along an axial axis of the rotaryvacuum chamber in a first direction such that the particles form atoroid on an inner wall of the rotary vacuum chamber (804). In someimplementations, controller (e.g., controller 170) is configured tooperate a drum motor (e.g., drum motor 130 a) to generate a rotarymotion in the rotary vacuum chamber (e.g., rotary vacuum chamber 112) ata rotational speed that is greater than a threshold rotational speedsuch that the particles form a toroid on an inner wall 150 of the rotaryvacuum chamber 112. A threshold rotation speed can be, for example, arotational speed of 10 RPM, 12 RPM, 15 RPM, or the like.

In some implementations, a controller is configured to operate a drummotor to generate a rotary motion of the rotary vacuum chamber at arotational speed of the rotary vacuum chamber that is less than athreshold rotational speed. For a rotational speed less than thethreshold rotational speed, the rotary vacuum chamber is rotated alongan axial axis of the rotary vacuum chamber in a first direction suchthat the particles fill a lower portion of the rotary vacuum chamberwhen the rotary vacuum chamber is rotating in the first direction (805).A rotational speed that is less than a threshold rotational speed canrange, for example, between 6-15 RPM. In one example, a lower portion180 of the rotary vacuum chamber 112 is filled with a particle bed 178such that as the rotary vacuum chamber 112 rotates in a first direction152, the particles in the particle bed 178 experience tumblingagitation. The rotary vacuum chamber is evacuated through a vacuum portin the rotary vacuum chamber aligned on the axial axis of the rotaryvacuum chamber (806). In some implementations, vacuum source 134evacuates the rotary vacuum chamber 112 via the stationary vacuumchamber 110 (e.g., through the filter 176) through the exhaust manifold134. A low-pressure environment can be established within the rotaryvacuum chamber 112, e.g., down to pressures below 1 Torr, e.g., to 1 to500 mTorr, e.g., 50 mTorr.

A paddle assembly is rotated in a second direction such that a pluralityof paddles orbit a drive shaft (808). In some implementations,controller 170 is configured to operate a paddle motor 130 b to generatea rotary motion of the paddle assembly 132 in a second direction 160 ata second rotational speed. The second direction of rotation of thepaddle assembly 132 can be in a same or opposite direction as the firstdirection of rotation of the rotary vacuum chamber 112.

The controller 170 can be configured to cause the paddle motor 130 a togenerate rotary motion of the paddle assembly 132 at rotational speedsup to 200 rpm.

A process gas is injected into the particles through a plurality of gasoutlets located on the plurality of paddles (810). In someimplementations, the reactor system performs an ALD and/or an MLDthin-film coating process by introducing gaseous precursors of thecoating into the rotary vacuum chamber 112. The gaseous precursors arespiked alternatively into the rotary vacuum chamber 112. This permitsthe deposition process to be a solvent-free process. The half-reactionsof the deposition process are self-limiting, which can provide Angstromor nanometer level control of deposition. In addition, the ALD and/orMLD reaction can be performed at low temperature conditions, such asbelow 50° C., e.g., below 35° C. Flow rates of the process gas can beselected based on a type of process gas being injected. For example, aflow rate for a H₂O process gas can be 1-2 standard liters per minute(slm) of vaporized precursor for 10 kg of powder. In another example, aflow rate for H₂O process gas could range between 0.5-1 slm for powderswith less surface area. In another example, TMA or TiCl₄ can havevolumetric flow rates, for example, less than 1 slm. In another example,carrier gas flow rates can be, for example, in the 1-3 slm range for10-15 kg of powder.

Suitable reactants for ALD methods include any of or a combination ofthe following: monomer vapor, metal-organics, metal halides, oxidants,such as ozone or water vapor, and polymer or nanoparticle aerosol (dryor wet). For example, the first fluid source 142 a can provide gaseoustrimethylaluminum (TMA) or titanium tetrachloride (TiCl4), whereas thesecond gas source 138 b can provide water. For MLD methods, as anexample, the fluid source 142 c can provide adipoyl chloride, and thefourth fluid 142 d can provide vaporous or gaseous ethylene diamine.

In some implementations, one of the process gasses flows from thechemical delivery system 122 into the particles 148 through the gasoutlets 166 located on the paddles 158 of the paddle assembly 132 as thepaddle assembly 132 rotates. Rotation of the paddle assembly 132agitates the particles to keep them separate, ensuring a large surfacearea of the particles remains exposed. This permits fast, uniforminteraction of the particle surface with the process gas.

For both an ALD process and an MLD process, two reactant gases arealternately supplied to the rotary vacuum chamber 112, with each step ofsupplying a reactant gas followed by a purge cycle in which the inertgas is supplied to the chamber 112 to force out the reactant gas andby-products used in the prior step.

In some implementations, the reactor system is operated in a continuousflow operation mode, e.g., for an ALD process. During an ALD process,the controller 170 can operate the reactor system (e.g., reactor systems100, 100′, 100′″) as follows. In a first reactant half-cycle, while thedrum motor 130 a rotates the rotary vacuum chamber 112 and paddle motor130 b rotates the paddle assembly 132 to agitate the particles 148:

i) The chemical distribution system 122 is operated to flow the firstreactant gas, e.g., TMA, from the source 138 a into the rotary vacuumchamber 112 via the gas outlets 166 located on the paddles 158 until theparticles 148 (e.g., particle bed 178) are saturated with the firstreactant gas. For example, the first reactant gas can flow at aspecified flow rate and for a specified period of time, or until asensor measures a specified first pressure or partial pressure of thefirst reactant gas in the chamber 112. In some implementations, thefirst reactant gas is mixed with an inert gas as it flows into thechamber. The specified pressure or partial pressure can be 0.1 Ton tohalf of the saturation pressure of the reactant gas. ii) Flow of thefirst reactant gas is halted, and the vacuum source 134 evacuates thechamber 112, e.g., down to pressures below 1 Ton, e.g., to 1 to 100mTorr, e.g., 50 mTorr.

These steps (i)-(ii) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, in a first purge cycle, while the drum motor 130 a rotates therotary vacuum chamber 112 and paddle motor 130 b rotates the paddleassembly 132 to agitate the particles 148:

iii) The chemical distribution system 122 is operated to flow only inertgas, e.g., N₂, from the source 138e into the chamber 112 via the gasoutlets 166 located on the paddles 158 of the paddle assembly 132. Theinert gas can flow at a specified flow rate and for a specified periodof time, or until a sensor measures a specified second pressure of theinert gas in the chamber 112. The second specified pressure can be 1 to100 Torr.

iv) The vacuum source 134 evacuates the chamber 112, e.g., down topressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (iii)-(iv) can be repeated a number of times set by therecipe, e.g., six to twenty times.

In a second reactant half-cycle, while the drum motor 130 a rotates therotary vacuum chamber 112 and paddle motor 130 b rotates the paddleassembly 132 to agitate the particles 148:

v) The chemical distribution system 122 is operated to flow the secondreactant gas, e.g., H₂O, from the source 138 b into the chamber 112 viathe gas outlets 166 located on the paddles 158 of the paddle assembly132 until the particles 148 are saturated with the second reactant gas.Again, the second reactant gas can flow at a specified flow rate and fora specified period of time, or until a sensor measures a specified thirdpressure or partial pressure of the second reactant gas in the chamber112. In some implementations, the second reactant gas is mixed with aninert gas as it flows into the chamber. The third pressure can be 0.1Torr to half of the saturation pressure of the second reactant gas.

vi) The vacuum source 134 evacuates the chamber 112, e.g., down topressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (v)-(vi) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, a second purge cycle is performed. This second purge cycle withsteps (vii) and (vii) can be identical to the first purge cycle, or canhave a different number of repetitions of the steps (iii)-(iv) and/ordifferent specified pressure.

The cycle of the first reactant half-cycle, first purge cycle, secondreactant half cycle and second purge cycle can be repeated a number oftimes set by the recipe, e.g., one to ten times.

The operation is discussed above with an ALD process, but the operationis similar for MLD. In particular, in steps (i) and (v), the reactantgasses are substituted with appropriate process gasses and pressures fordeposition of a polymer layer. For example, step (i) can use vaporous orgaseous adipoyl chloride, and step (v) can use are vaporous ethylenediamine.

Moreover, although operation is discussed above with an ALD or MLDprocess, the system could be used for a chemical vapor deposition (CVD)process. In this case, both reactants are flowed simultaneously into thechamber 110 so as to react inside the chamber, e.g., during step (i).The second reactant half-cycle can be omitted.

In some implementations, the reactor system (e.g., reactor system 100,100′, 100′″) is operated in a pulsed flow operation mode, where one ormore of the gases (e.g., the reactant gases and/or the inert gas) can besupplied in pulses in which the chamber 112 is filled with the gas to aspecified pressure, a delay time is permitted to pass, and the chamberis evacuated by the vacuum source 134 before the next pulse commences.

In particular, for an ALD process, the controller 170 can operate thereactor system 100 as follows.

In a first reactant half-cycle, while the drum motor 130 a rotates therotary vacuum chamber 112 and paddle motor 130 b rotates the paddleassembly 132 to agitate the particles 148:

i) The chemical distribution system 122 is operated to flow the firstreactant gas, e.g., TMA, from the source 138 a into the chamber 112 viathe gas outlets 166 located on the paddles 158 of the paddle assembly132 until a first specified pressure is achieved in the chamber 112. Thespecified pressure can be 0.1 Torr to half of the saturation pressure ofthe reactant gas.

ii) Flow of the first reactant gas is halted, and a specified delay timeis permitted to pass, e.g., as measured by a timer in the controller.This permits the first reactant to flow through the particles 148 in therotary vacuum chamber 112 and react with the surface of the particles.

iii) The vacuum source 134 evacuates the chamber 112, e.g., down topressures below 1 Torr, e.g., to 1 to 100 mTorr, e.g., 50 mTorr.

These steps (i)-(iii) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, in a first purge cycle, while the drum motor 130 a rotates therotary vacuum chamber 112 and paddle motor 130 b rotates the paddleassembly 132 to agitate the particles 148:

iv) The chemical distribution system 122 is operated to flow the inertgas, e.g., N₂, from the source 138 e into the chamber 112 via the gasoutlets 166 located on the paddles 158 of the paddle assembly 132 untila second specified pressure is achieved. The second specified pressurecan be 1 to 100 Torr.

v) Flow of the inert gas is halted, and a specified delay time ispermitted to pass, e.g., as measured by the timer in the controller.This permits the inert gas to diffuse through the particles in theparticle bed 10 to displace the reactant gas and any vaporousby-products.

vi) The vacuum source 132 evacuates the chamber 112, e.g., down topressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (iv)-(vi) can be repeated a number of times set by therecipe, e.g., six to twenty times.

In a second reactant half-cycle, while the drum motor 130 a rotates therotary vacuum chamber 112 and paddle motor 130 b rotates the paddleassembly 132 to agitate the particles 148:

vii) The chemical distribution system 122 is operated to flow the secondreactant gas, e.g., H₂O, from the source 138 b into the chamber 112 viathe gas outlets 166 located on the paddles 158 of the paddle assembly132 until a third specified pressure is achieved. The third pressure canbe 0.1 Torr to half of the saturation pressure of the reactant gas.

viii) Flow of the second reactant gas is halted, and a specified delaytime is permitted to pass, e.g., as measured by the timer in thecontroller. This permits the second reactant gas to flow through theparticles 148 and react with the surface of the particles inside therotary vacuum chamber 112.

ix) The vacuum source 134 evacuates the chamber 112, e.g., down topressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (vii)-(ix) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, a second purge cycle is performed. This second purge cycle can beidentical to the first purge cycle, or can have a different number ofrepetitions of the steps (iv)-(vi) and/or different delay time and/ordifferent pressure.

The cycle of the first reactant half-cycle, first purge cycle, secondreactant half cycle and second purge cycle can be repeated a number oftimes set by the recipe, e.g., one to ten times.

Moreover, one or more of the gases (e.g., the reactant gases and/or theinert gas) can be supplied in pulses in which the rotary vacuum chamber112 is filled with the gas to a specified pressure, a delay time ispermitted to pass, and the chamber is evacuated by the vacuum source 134before the next pulse commences.

The operation is discussed above with an ALD process, but the operationis similar for MLD. In particular, in steps (i) and (vii), the reactantgasses are substituted with appropriate process gasses and pressures fordeposition of a polymer layer. For example, step (i) can use vaporous orgaseous adipoyl chloride, and step (vii) can use are vaporous ethylenediamine.

Moreover, although operation is discussed above with an ALD or MLDprocess, the system could be used for a chemical vapor deposition (CVD)process. In this case, both reactants are flowed simultaneously into thechamber 110 so as to react inside the chamber, e.g., during step (i).The second reactant half-cycle can be omitted.

As noted above, the coating process can be performed at low processingtemperature, e.g., below 50° C., e.g., at or below 35° C. In particular,the particles 148 can remain or be maintained at such temperaturesduring all of steps (i)-(ix) noted above. In general, the temperature ofthe interior of the reactor chamber does not exceed 35° C. during ofsteps (i)-(ix). This can be achieved by having the first reactant gas,second reactant gas and inert gas be injected into the chamber at suchtemperatures during the respective cycles. In addition, physicalcomponents of the chamber of the chamber can remain or be maintained atsuch temperatures, e.g., using a cooling system, e.g., a thermoelectriccooler, if necessary.

In some implementations, the controller can cause the reactor system 100to first deposit a metal oxide layer on the drug-containing particles,and then deposit a polymer layer over the metal oxide layer on theparticles, e.g., using the process described above. In someimplementations, the controller can cause the reactor system 100alternate between depositing a metal oxide layer and depositing apolymer layer on the drug-containing particles, so as to form amulti-layer structure with layers of alternating composition.

The controller 170 and other computing devices part of systems describedherein can be implemented in digital electronic circuitry, or incomputer software, firmware, or hardware. For example, the controllercan include a processor to execute a computer program as stored in acomputer program product, e.g., in a non-transitory machine readablestorage medium. Such a computer program (also known as a program,software, software application, or code) can be written in any form ofprogramming language, including compiled or interpreted languages, andit can be deployed in any form, including as a standalone program or asa module, component, subroutine, or other unit suitable for use in acomputing environment. In some implementations, the controller 105 is ageneral purpose programmable computer. In some implementations, thecontroller can be implemented using special purpose logic circuitry,e.g., an FPGA (field programmable gate array) or an ASIC (applicationspecific integrated circuit).

For a system of one or more computers to be configured to performparticular operations or actions means that the system has installed onit software, firmware, hardware, or a combination of them that inoperation cause the system to perform the operations or actions. For oneor more computer programs to be configured to perform particularoperations or actions means that the one or more programs includeinstructions that, when executed by data processing apparatus, cause theapparatus to perform the operations or actions. The present disclosureprovides apparatus for and methods of preparing pharmaceuticalcompositions comprising API containing particles encapsulated by one ormore layers of metal oxide and/or one or more layers of a polymer. Thecoating layers are conformal and of controlled thickness from severalnanometers to several micrometers in total. The articles to be coatedcan be composed of only API or a combination of API and one or moreexcipients. The coating process described herein can provide an API withan increased glass transition temperature for the API relative touncoated API, a decreased rate of crystallization for an amorphous formof the API relative to uncoated API, and decreased surface mobility ofAPI molecules in the particle compared to uncoated API. Importantly,particle dissolution can be altered. Because the coating is relativelythin, drug products with high drug loading can be achieved. Finally,there are benefits with respect to cost and ease of manufacture becausemultiple coatings can be applied in the same reactor.

Terms of relative positioning are used to refer to relative positioningof components within the system or orientation of components duringoperation; it should be understood that the reactor system could be heldin a vertical orientation or some other orientation during shipping,assembly, etc.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

What is claimed is:
 1. A method for coating particles, comprising:dispensing particles into a rotary vacuum chamber; rotating the rotaryvacuum chamber along an axial axis of the rotary vacuum chamber in afirst direction; evacuating the rotary vacuum chamber through a vacuumport in the rotary vacuum chamber rotating a paddle assembly in a seconddirection such that a plurality of paddles orbit a drive shaft; andinjecting a process gas into the particles through a plurality of gasoutlets located on the plurality of paddles wherein, as the plurality ofpaddles orbit, at least one gas outlet of the plurality of gas outletsis located within a particle bed formed by the particles to percolatethe process gas through the particles held within the rotary vacuumchamber.
 2. The method of claim 1, wherein injecting the process gasinto the particles through the plurality of gas outlets furthercomprises delivering the process gas via chemical supply passageslocated within the paddle assembly.
 3. The method of claim 2, whereinthe chemical supply passages deliver the process gas through a baseshaft and plate portion of one or more paddles of the plurality ofpaddles.
 4. The method of claim 1, wherein the vacuum port is aligned onthe axial axis of the rotary vacuum chamber.
 5. The method of claim 1,wherein rotating the rotary vacuum chamber along the axial axis of therotary vacuum chamber in the first direction comprises: rotating acylindrical portion of the rotary vacuum chamber at a rotation speedless than a threshold rotational speed such that a portion of theparticles dispensed within the rotary vacuum chamber provide a particlebed that remains in a lower portion of the rotary vacuum chamber.
 6. Themethod of claim 5, wherein rotating the rotary vacuum chamber along theaxial axis of the rotary vacuum chamber in the first directioncomprises: rotating the cylindrical portion of the rotary vacuum chamberat a rotation speed such that the particles undergo tumbling agitation.7. The method of claim 6, wherein the rotation speed is about 6-15 RPM.8. The method of claim 1, wherein rotating the rotary vacuum chamberalong the axial axis of the rotary vacuum chamber in the first directioncomprises: rotating a cylindrical portion of the rotary vacuum chamberat a rotation speed greater than a threshold rotational speed such thatthe particles form a toroidal bed of particles on an inner wall of therotary vacuum chamber.
 9. The method of claim 8, wherein at least one ofthe plurality of gas outlets is located on a portion of a paddle of theplurality of paddles within the toroidal bed of particles as theplurality of paddles orbit about the drive shaft.
 10. The method ofclaim 8, wherein the rotation speed is greater than 15 RPM.
 11. Themethod of claim 10, wherein a rotation speed of the drive shaft relativeto the rotary vacuum chamber about the axial axis is at least 4 rpm. 12.The method of claim 1, comprising coating the particles by atomic layerdeposition or molecular layer deposition.
 13. The method of claim 1,comprising coating the particles by initiated chemical vapor deposition.14. The method of claim 1, wherein the particles comprise an activepharmaceutical ingredient.
 15. The method of claim 12, wherein theparticles comprise a core containing a drug.
 16. The method of claim 1,further comprising depositing an organic or inorganic coating over theparticles.
 17. The method of claim 16, wherein the organic or inorganiccoating comprises an inorganic metal oxide.
 18. The method of claim 16,wherein the organic or inorganic coating comprises an organic polymer.19. The method of claim 1, wherein the first direction is opposite ofthe second direction.